Which studies at IAS will have the most impact in terms of changing clinical practice?

Probably the things that are going to change clinical practice are going to be presented later on today, the late breakers. So I actually haven't seen those data yet. But from what I've heard, very encouraging information is going to be presented on maraviroc [MVC, Selzentry, Celsentri], the CCR5 inhibitor. Over the last couple days, we have seen confirmation that some of the drugs which are now available on expanded access, including maraviroc, as well as raltegravir [MK-0518, Isentress] and etravirine [TMC125, Intelence], are both safe and very effective.

From my perspective, these are the biggest things that are going to affect clinical practice. None of this research is all that new. These are more or less updates on some of the stuff that's been recently published, and some of the stuff we saw at CROI [Conference on Retroviruses and Opportunistic Infections] a few months ago.

But as with all these major meetings, at the end of the day, things that clinicians like myself go back with, is new information on these new drugs. It's all quite positive.

Have you changed when you start people on therapy? If so, why?

Yes, sure. Over the past year or so, there have been a number of studies on this subject. The first study, the SMART study,1 included data from some of the large European cohorts, which have clearly shown a relationship between CD4 count and the risk of non-AIDS events -- basically, cardiovascular disease, kidney disease, liver disease, and so forth. The data suggest that it doesn't take much of a CD4 loss for patients to become at risk for these events. If my goal is to ensure that my patient has a normal lifespan, that my patient actually is able to avoid any HIV-associated complications, then I think it's actually key, whenever possible to keep CD4 counts as high as possible, basically above 500 cells.

The best way to do that is to initiate treatment early. Treatment has side effects, and a lot of people are just not into treatment. So it's also pretty clear that, although these effects are real, that these risks are real, they are not dramatic. To a certain degree, in some people I'm certainly willing to defer therapy. But because treatment is so effective at preventing AIDS and AIDS-related mortality, we now need to be other questions: How can we ensure that patients actually get a normal lifespan?

From my perspective, it's pretty clear that the earlier you initiate therapy, the more likely you are to achieve that. So for people who are willing and able to access medications, I encourage therapy as early as possible.

Is there a magic number?

No. No. There's no magic number.

So it's not like 800 T cells?

Oh, no, no, no, no. People with HIV infection generally come into the clinic with early stage disease. We take our time...unless it's acute infection. If it's chronic infection -- but early-stage HIV disease, with high CD4 counts -- we discuss the pros and cons, take some time, and make a decision.

For a lot of people, the constant reminder of being HIV-infected, or the mild side effects -- that can have an impact on the quality of life such that, in my mind, it's very reasonable to defer therapy. It really is basically balancing the risks and benefits of therapy, and individualizing.

In the last couple of years, I have often encouraged people to start earlier. But there's no magic number. If there is a magic number, it's basically 350. I encourage people to start treatment, but I don't really push it, until the CD4 count gets below 350.

So 350 is the new 200.

That's well put. Well put.

Is there any trial right now in process to show when to initiate treatment?

The NIH [National Institutes of Health] and NIAID [National Institute of Allergy and Infectious Diseases] are going to sponsor a large pilot study, with about 1,500 individuals, in the INSIGHT network [International Network for Strategic Initiatives in Global HIV Trials]. People who have CD4 counts over around 450 to 500 are going to be randomized to start now, versus waiting until the count drops to 350. That study will hopefully provide at least evidence that such a study can be done, and may provide preliminary insights into whether early therapy is actually worth doing.

But everything I have discussed, and the reason I've changed my opinion, is based largely on non-randomized clinical trials, and therefore is really not definitive.

Can we switch gears? Yesterday we heard results of the SMART study subanalysis that showed that more deaths occurred in the hepatitis B or C group.2 Can you comment on this?

I think there have been a couple of really important things that have come out of the SMART. One is that people with hepatitis B typically do unusually poorly when they stop drugs. The reason for that has to be defined.

It does remind us that hepatitis B is a significant infection that is actually often treated with the same drugs, and that stopping drugs for HIV can also lead to hepatitis B-related consequences, which can clearly be bad for the liver, but also appear, for whatever reason, to be bad for the immune system. So the management of people coinfected with hepatitis B and HIV is much more complicated, and there's much more stronger rationale for such people to remain on therapy.

The other interesting thing that came from the conference -- and I actually think it's the most interesting thing at this meeting is the information that, again, came from the SMART study,3 showing that D-dimers, which are part of the coagulation process, appear to be independently predicting the risk of overall mortality, as well as these non-AIDS events. From a pathogenesis perspective, these data provide, and make some very interesting results, as well as opportunity for novel research questions.

Could you explain that a little bit more?

One of the biggest puzzles over the last couple of years is why people with HIV disease are at high risk for cardiovascular events. The leading hypothesis is that there is something wrong with the coagulation process that results in an increased likelihood of developing thrombosis, which can lead to heart attacks, and so forth.

In the SMART study, the researchers went back and looked at these factors associated with coagulation -- and one of them is D-dimers -- and found that, yes indeed, D-dimers are higher in people with HIV infection. They go up when you stop drugs. They go down when you restart drugs. They are associated with an increased risk of cardiovascular disease.

All of that may not be all that surprising, but what is really interesting is that these D-dimers -- which are associated with thrombosis, clotting, and so forth -- also tend to be predictive of many other things in HIV disease. The question is, why?

Are they still looking at this?

Oh, yes. Over the next year or two, people are going to be looking at this much more carefully. It may end up being that this is all related to the T-cell activation/inflammation theory, which is that HIV, at the end of the day, is a proinflammatory process, and as a consequence of inflammation, T-cell activation, and so forth, people who are at high risk are getting all sorts of bad events. This may be part of that story.

There were a lot of poster presentations yesterday about metabolic complications. Was there anything of interest?

I did not go to those sessions.

Okay. And I guess a final question I have is about is about HIV eradication. There was a report by Fauci in one of the journals4 where he intimated that we are closer to HIV eradication than ever before. Can you comment on that?

This concept of eradication or cure is one of the most important areas for which we need more research. Tony Fauci's group recently published in the Journal of Infectious Diseases that if you start antiretroviral therapy early, you are more likely to accelerate, or you have a more rapid rate of, getting rid of the virus with therapy -- arguing for earlier therapy. Whether or not this can lead to a cure remains unknown. There's a lot more buzz these days about eradication, because the drugs that were used in the past to suppress the virus may not have been as potent as the current generation of drugs, particularly the integrase inhibitors, like raltegravir.

So it's reasonable to go back and think that, with more potent drugs, we may be able to actually shut down virus replication even more completely. As a consequence, can we actually accelerate the process of viral decay, leading to eradication? Highly unlikely, but it's worth talking about, and thinking about.

Why do we think that the drugs today are more potent? Is it because people's viral loads become undetectable sooner, for instance with raltegravir?

Basically, yes. This is all being driven by the fact that the viral load drops much more rapidly with the Merck integrase inhibitor than with drugs in the past. Whether that is completely due to potency or other factors remains unclear.

So there's not a lot of evidence, really.

Not a lot of evidence, but it's suggestive, and it's worthy of further research.

One last question: What do you think are the biggest open questions in HIV research?

In terms of therapeutics, the biggest questions are when to start, which drugs to start with, and when and how to switch [treatment regimens]. Another major question is: to what degree are the drugs that are being used in Europe, North America and so forth, going to apply in resource-poor areas, where there are a lot of other factors that can have an impact on treatment. Basically, those are the major issues.

The other major one would be what to do with all these long-term HAART-treated patients whose CD4 counts never went back up to normal. These are the main questions. They are not all that different from the questions we've been dealing with for the past few years.

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